Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis
| Autor: | Aberra Fura, Shiuhang Yip, Georgia Cornelius, Hai-Yun Xiao, Qingjie Liu, Sha Li, Ning Li, Nicholas A. Meanwell, Shailesh Dudhgaonkar, Max Ruzanov, Jenny Xie, Zili Xiao, Purnima Khandelwal, Carolyn A. Weigelt, David J. Shuster, Dauh-Rurng Wu, T. G. Murali Dhar, Tara Sherry, Yang Michael G, Kevin Stefanski, Jignesh Nagar, Rex Denton, Qihong Zhao, Peng Li, Silvi A. Chacko, Arun Govindarajan, Robert M. Borzilleri, John S. Sack, Yeheng Zhu, Yunling Song, Dawn Sun, Anjuman Rudra, Mary T. Obermeier, Jinhong Wang, Douglas G. Batt, Venkata Murali |
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| Rok vydání: | 2021 |
| Předmět: |
Membrane permeability
010405 organic chemistry Chemistry Organic Chemistry Pharmacology medicine.disease 01 natural sciences Biochemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry In vivo RAR-related orphan receptor gamma Psoriasis Rheumatoid arthritis Drug Discovery medicine Potency Inverse agonist |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] Structure–activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5–7. The hexahydropyrrolo[3,2-f]quinoline series 5 (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis. |
| Databáze: | OpenAIRE |
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